The preparations containing an active ingredient used in the fields of pharmaceuticals, agricultural chemical, fertilizers feed, food, industries, cosmetics, etc., are desired, in many cases, to be quickly disintegrated for the immediate expression of active ingredient effects when placed in an intended environment. Conventionally, disintegrants are generally used to improve the disintegrating properties of these solid preparations. Examples of the disintegrant include cellulose derivatives such as carmellose calcium (calcium carboxymethyl cellulose), croscarmellose sodium (crosslinked sodium carboxymethyl cellulose), cellulose derivatives such as low substituted hydroxypropyl cellulose, chemical synthetics such as crospovidone (crosslinked polyvinyl pyrrolidone), starch derivatives such as carboxymethyl starch sodium and hydroxypropyl starch, plant rubbers such as guar gum and sodium alginate, and starches such as partly pregelatinized starch.
However, metal salts such as carmellose calcium, croscarmellose sodium, hydroxypropyl starch were not always satisfactory because, when mixed with an active ingredient, or the like, showing the reactivity to a metal salt, the active ingredient is decomposed during storage resulting in a reduced content, coloring, or the like. Further, hydroxypropyl starch, low substituted hydroxypropyl cellulose, and like celluloses or starch polymers in which a hydrophobic substituent is introduced are nonionic but the hydrophobic substituent itself was sometimes reactive to a drug. For this reason, the problems such as the decomposition of an active ingredient or the development of coloring during storage were posed and thus they were not always satisfactory. Furthermore, crospovidone (crosslinked polyvinyl pyrrolidone) is considered to have a comparatively low interaction with a drug but is characterized as being highly hygroscopic. Thus, crospovidone had drawbacks in that the decomposition of an active ingredient was caused which was promoted by the presence of moisture such as the ester bond, a solid preparation was swollen due to the moisture absorption and stuck to other solid preparations or a container, the hardness and friability of a solid preparation were reduced, or the like. The tablet in a PTP package, when absorbing moisture over time causing the reduction of hardness, becomes useless for practical application due to the occurrence of the breakage or cracks. Further, since crospovidone is a chemically polymerized product, a monomer (vinyl pyrrolidone) toxic to human body and a chemical contaminant (hydrazine) are mixed in, which hence has been problematic. Sodium alginate, agar, and the like, have not been in much use as a disintegrant because they have drawbacks as being expensive, having poor compression properties, and the like.
Starches, represented by raw starch (β-starch) and partly pregelatinized starches in which a part of raw starches are gelatinized, have been used as disintegrants which are less reactive to a drug and have low hygroscopicity. The processed starches, in which raw starch is physically modified, have been widely used as disintegrants because the starch swelling properties can be enhanced by a method such as changing the level of gelatinization, or the like, they have a low reactivity to an active ingredient due to chemically being the same as raw starch, they are inexpensive, and they have been commonly eaten and very safe. However, these starches (PATENT DOCUMENTS 1 to 9 and 11 to 19), compared with synthetic products such as croscarmellose sodium, crospovidone, etc., have poorer disintegrating properties and thus require to be added in a large amount for imparting satisfactory disintegrating properties, consequently limiting the amount of an active ingredient to be added.
PATENT DOCUMENT 1 describes that a processed starch having a swelling degree (which corresponds to the water retention capacity of the present invention) of 3.0 to 6.0 can be used as a disintegrant, however; the swelling degree is 3.0 to 6.0 and is different from the range of the present invention. According to PATENT DOCUMENT 1, the processed starch is obtained by a method in which a starch is completely gelatinized by being extruded at a low pressure using an extruder having a small screw compression ratio, or like method, subsequently cooled to crystallize a part of the gelatinized starches, followed by being dried and crushed to adjust the particle size. Accordingly, since such a processed starch has at least a part of the starch particles broken due to the mechanical force applied during the gelatinization process and hence the outer shell structure damaged, the stress applied to the surroundings by the swell is diminished, thereby providing insufficient disintegrating force. The disintegration time of the tablet used in Examples of this PATENT DOCUMENT is 3.9 to 8.3 minutes when the processed starch is added in an amount of 10% by weight, whereas the disintegration time is 20 seconds or less when the processed starch powder of the present invention is used in the same formula. Thus, the processed starch described in PATENT DOCUMENT 1 is clearly different in the disintegrating force from the processed starch of the present invention. The processed starch of the present invention is effective even when added in an amount of 5% by weight or less. The method described in PATENT DOCUMENT 1 also differs from the present invention in the aspect of comprising a cooling step after heating.
PATENT DOCUMENT 2 describes an aggregate of a natural starch and a pregelatinized starch which contains 1 to 20% by weight of the pregelatinized starch and 80 to 99% by weight of the natural starch, and has a size of 100 to 500 μm. Since the processed starch of the present invention has an average particle size of the primary particles of 25 to 80 μm and most of the particles do not form aggregates, it is different from PATENT DOCUMENT 2 in the aspect of the size of dry particles. Further, the aggregate of this invention of PATENT DOCUMENT 2 is formed by granulating the pregelatinized starch and the natural starch, and is hence also clearly different from the present invention in that the birefringent property intrinsic to the natural starch is observed. PATENT DOCUMENT 3 describes a starch granule in which β-starch is mutually bonded with 1 to 4% by weight of pregelatinized starch grains, but the starch granule is different from the processed starch of the present invention in that the birefringent property intrinsic to the β-starch is observed. Further, the invention of the above document is also different from the present invention in the aspect of mixing the β-starch and a pregelatinized starch aqueous solution (a state of mist droplet) and in the aspect of not including a heating process. Furthermore, the amounts of the starch granule added in Examples of said PATENT DOCUMENT are required as much as 17% by weight and 87% by weight, whereas the processed starch of the present invention can impart sufficient disintegrating properties even when added in an amount of 5% by weight or less. PATENT DOCUMENT 4 discloses a method for producing a granule and a tablet by the granulation and compression using as a binder and a disintegrant β-starch with the surface being gelatinized, and PATENT DOCUMENT 5 discloses a method for producing β-starch with the surface being gelatinized. However, the starch of PATENT DOCUMENT 4 comprises 60% by weight of the β-starch and the starch of PATENT DOCUMENT 5 comprises 80 to 95% by weight of the β-starch, exhibiting the birefringent property intrinsic to the β-starch. In these aspects, these starches are different from the processed starch of the present invention. The β-Starch is treated using steam at 100 to 120° C. and immediately fluidized bed dried in PATENT DOCUMENTS 4 and 5, whereas the present invention includes a step of heat treatment using steam at 100 to 130° C. under a reduced pressure condition to prepare a starch slurry and a step of further heating the starch slurry, followed by drying (spray drying). Thus, the present invention is also different in this regard from PATENT DOCUMENTS 4 and 5. The amount of the starch granule added in Examples of these PATENT DOCUMENTS is required as much as 30% by weight, whereas the processed starch of the present invention can impart sufficient disintegrating properties even when added 5% by weight or less. Since natural or β-starch powder has particles having a swelling ratio of as small as about 1.2 times or less and the disintegrating force is hence low, the processed starches of PATENT DOCUMENTS 2 to 5 consisted largely of these particles fail to attain a sufficient disintegrating force and are clearly different from the processed starch of the present invention having a particle swelling ratio of 1.5 time or more with a good disintegrating force.
PATENT DOCUMENT 6 discloses a processed starch powder which practically preserves the outer shell structure, contains 10% by weight or less of a cold water soluble component (which corresponds to the water soluble component of the present invention), has a swelling volume (which corresponds to the sedimentation volume of the present invention) of 3 to 15 ml/g and a water retention potential of about 2 or higher. Further, PATENT DOCUMENT 7 discloses a starch powder containing less than 10% by weight of a cold water soluble component (which corresponds to the water soluble component of the present invention), having a swelling volume (which corresponds to the sedimentation volume of the present invention) of 5 to 15 ml/g and having more nonbirefringent particles than birefringent particles. The processed starches of PATENT DOCUMENTS 6 and 7 are those heat-treated in the presence of water at a temperature of about 10° C. higher than the gelatinization temperature intrinsic to the starch or lower, and imparted with enhanced swelling properties without breaking the starch particles. However, in PATENT DOCUMENTS 6 and 7, since the heating temperature is as low as a temperature of about 10° C. higher than the gelatinization temperature or lower, the effect to enhance the swelling properties of the starch particles was little. The swelling ratio of the processed starch powder made from cornstarch obtained by the methods described in PATENT DOCUMENTS 6 and 7 was as small as about 1.3 and the disintegration time of the tablet was significantly long compared with that of the processed starch of the present invention (see Comparative Example 8 in the present application). In Example 17 of PATENT DOCUMENT 6 in which potato starch was used as a raw material as in the present invention, it is described that the particles were damaged and the water retention capacity exceeded 1500%. Thus, the invention of PATENT DOCUMENT 6 is different from the present invention in the condition of the outer shell structure and the water retention capacity. Further, when Example 15 of PATENT DOCUMENT 7 in which potato starch was similarly used as a raw material was reexamined, the average particle size of the primary particles in the swollen state in water was as small as 35 μm since the heating temperature is as low as a temperature of about 10° C. higher than the gelatinization temperature or lower, resulting in poorer disintegrating properties than the processed starch of the present invention (see Comparative Example 1 of the present invention). The processed starch powders of PATENT DOCUMENTS 6 and 7 are obtained by heating raw starch in the presence of water at a temperature ranging from 50° C. to a temperature of about 10° C. higher than the gelatinization onset temperature or lower, that is one-stage heat treatment, whereas the processed starch of the present invention is obtained by heat-treating a natural starch material (which corresponds to the raw starches in PATENT DOCUMENTS 6 and 7) using steam at a temperature ranging from 100° C. or higher to 130° C. or lower under reduced pressure conditions, subsequently preparing a starch slurry having a solid content of 1 to 20% by weight (which corresponds to the in the presence of water in PATENT DOCUMENTS 6 and 7) and heat-treating at a temperature range from more than a temperature of 10° C. higher than the gelatinization onset temperature intrinsic to starch to less than 90° C., that is two-stage heating of raw starch. Therefore, the processed starch of the present invention is clearly different from those of PATENT DOCUMENTS 6 and 7. Also, the present invention is definitely different in that the temperature range for the heat treatment of the starch slurry, i.e., in the presence of water, is higher than that of PATENT DOCUMENTS 6 and 7.
PATENT DOCUMENT 8 describes an excipient which consists of crystalline cellulose and a modified starch. The modified starch has completely different particle structure from the processed starch of the present invention in the aspects that it does not have the outer shell structure of raw starch due to a partial breakage of the particles caused by the downsizing and that the distinct polarized cross as in cornstarch is found (see FIG. 2 of the PATENT DOCUMENT). Further, since this modified starch contained 10 to 20% by weight of a cold water soluble component (which corresponds to the water soluble component of the present invention) which is more than that of the processed starch of the present invention, the cold water soluble component was dissolved and an adhesive film was formed on the surface or in the pore of a tablet, whereby the permeation of water into a solid preparation was inhibited and a sufficient disintegrating force was not attained. Further, the production method is also different from that of the present invention in the respect of applying a pressure in the presence of water and not including the heating.
PATENT DOCUMENT 9 discloses a processed starch which is mechanically modified, partially pregelatinized, has a sedimentation volume of 1.5 to 9 ml/g and a cold water solubility (which corresponds to the water soluble component of the present invention) of 1 to 8% by weight. The processed starch has most of the particles formed by the continuous engagement of the birefringent part and the mechanically modified nonbirefringent part and hence practically being birefringent particles showing the polarized cross (see FIG. 1 of the PATENT DOCUMENT) which is different from the present invention in the particle structure. The nonbirefringent part in which the outer shell structure of the mechanically modified particle is disrupted has a diminished stress to the surroundings of the starch particle when it absorbs water and swells, and the birefringent part which is not mechanically modified has the swelling properties only equivalent to that of raw starch. For this reason, the processed starch of PATENT DOCUMENT 9 which is the mixture of these particles consequently had a diminished disintegrating force. Further, the starch particle of this invention has an individual starch particle size of as small as 20 μm in water, and hence it is different from the processed starch of the present invention which has the particle size of 50 to 120 μm. Furthermore, as evident from FIG. 3 of PATENT DOCUMENT 9, the swelling ratio of the particles (due to the engagement of several particles there are undistinguishable primary particles derived from the natural starch but the swelling ratio was calculated by selecting only the distinguishable primary particles) is as small as 1.1, and hence the processed starch of PATENT DOCUMENT 9 is different from the processed starch of the present invention having a particle swelling ratio of 1.5 or more. The swelling ratio was the same as that of commercial Starch 1500 (see Comparative Example 7 of the present application). The starch described in this PATENT DOCUMENT is obtained by the extrusion at a formation temperature of 50 to 110° C. and this starch is obviously different in the production method from the present invention. Still furthermore, the amount of the starch granule added in Examples of the PATENT DOCUMENT is required as much as 74.8% by weight, whereas the processed starch of the present invention can impart sufficient disintegrating properties even when added in an amount of 5% by weight or less.
PATENT DOCUMENT 11 discloses a starch powder which is treated by direct compression, partially swollen and has a ratio of non-swelling birefringent particle to swelling nonbirefringent particle of 1:5 to 5:1. Further, PATENT DOCUMENT 12 discloses a preparation comprising partially swollen starch powder containing nonbirefringent starch granule and non-swelling birefringent starch granule in a ratio of 1:5 to 5:1. The processed starches of PATENT DOCUMENTS 11 and 12 are different from the processed starch of the present invention in the aspect that they contain non-swelling birefringent particles in a proportion of one sixth or more, i.e., exceeding 10%, whereas the processed starch of the present invention contains 90% or more of the particles being swelling nonbirefringent particles in which the polarized cross is disappeared. The processed starches of PATENT DOCUMENTS 11 and 12 are the same as that of the present invention in the aspect that they are obtained by heat-treating a starch slurry to cause a partial swelling of the starch grain without disintegrating the starch grain. However, since the heating is carried out at a temperature practically not higher than the gelatinization temperature of the starch, it is difficult to reduce the crystallinity of the starch particle and enhance the swelling properties and, as a result, the non-swelling birefringent particles are contained in a proportion of one sixth or more, i.e., exceeding 10%. Since the non-swelling birefringent starch has almost or totally no disintegrating force, the processed starches of PATENT DOCUMENTS 11 and 12 which contain a large amount of the non-swelling birefringent particles exhibited little disintegrating force. Further, the amount of the starch granule added in Examples of these PATENT DOCUMENTS is required as much as 19 to 59% by weight, whereas the processed starch of the present invention can impart sufficient disintegrating properties even when added in an amount of 5% by weight or less.
PATENT DOCUMENTS 13 and 14 disclose a downsized starch having the particle being crushed due to the downsizing, containing about 4 to 40% by weight of a cold water soluble component (which corresponds to the water soluble component of the present invention) and having a swelling force (which corresponds to the sedimentation volume of the present invention) of 2.5 to 12. Such a processed starch has its particle partially crushed by the downsizing and is different from the processed starch of the present invention in which only the outer shell structure derived from raw starch is preserved, the particle is not crushed and the shape of the starch particle is maintained. The processed starch in which the particles are partially crushed irreversibly swells (dissolves) in water. As a result, the viscosity of a liquid is increased and an adhesive film is formed on the surface or in the pore of a tablet, thereby inhibiting the permeation of water into a solid preparation and failing to achieve a sufficient disintegrating force. Further, the dissolved product posed problems such as the intense reactivity to an active ingredient which developed the coloring of the composition over time, or the like. Furthermore, as shown in FIGS. 2 and 4 of this PATENT DOCUMENT, the birefringent part of the downsized starch exhibits a distinct polarized cross as seen in raw cornstarch. The starch particle having such high crystallinity that the polarized cross is clearly seen had poor swelling properties and failed to achieve a sufficient disintegrating force. The tablet shown in Examples of PATENT DOCUMENTS 13 and 14 contains such a downsized starch in a large amount of 50% by weight or more and is different in the aspect of the disintegrating force from the processed starch of the present invention which is capable of expressing a sufficient disintegrating force when added in an amount of 1 to 5% by weight.
PATENT DOCUMENT 15 discloses a method for producing a tablet containing powder or granular waxy cornstarch. However, the waxy cornstarch of this invention is a natural raw starch itself and has the birefringent properties, and hence it is different from the processed starch of the present invention. The starch composed of solely birefringent particles has an insufficient disintegrating force. As shown in Examples of this PATENT DOCUMENT, such a processed starch requires waxy cornstarch as much as 50% by weight of the tablet and is different in this respect from the processed starch of the present invention which exhibits a sufficient disintegrating force when added in an amount of 1 to 5% by weight.
Further, waxy cornstarch is known to contain 100% by weight of amylopectin which is also different from the processed starch of the present invention wherein the amylopectin content never be 100% by weight because a natural starch containing 20% by weight or more and less than 30% by weight of amylose is used in the present invention.
PATENT DOCUMENT 16 discloses a processed starch which has a water retention capacity of 400% or higher, a disintegration time of 5 hours or more and, when dispersed in water, has 10 to 90% by weight of amylose and amylopectin (which corresponds to the amount of the water soluble component of the present invention) present in the swollen or dissolved state. This processed starch has 10 to 90% by weight of amylose and amylopectin present in the swollen or dissolved state, i.e., the amount of water soluble components, and is different from the present invention in the aspect of the amount range of the water soluble components. This PATENT DOCUMENT further describes steps of further heating at 60 to 150° C. in the presence of water a starch material heat-treated using steam at 100 to 130° C. under a reduced pressure and swelling the starch particles of the starch material, and steps of subsequently drying the swollen starch particles and obtaining a mixture comprising the starch particle, and amylose and amylopectin present outside the starch particle. However, in Examples in which the above steps were carried out, the heat treatments were performed in the presence of water at a temperature of 95 to 120° C., exceeding 90° C., and the production method of this document is different from that of the present invention in the aspect of, i.e., the temperature for heating in the presence of water at the step after a starch slurry is prepared. In this PATENT DOCUMENT, as a result of the heat treatment at a temperature exceeding 90° C., the outer shell structure derived from raw starch is destructed as described to read amylose and amylopectin present outside the starch particle, and the water soluble components are contained in an amount of 10% by weight or more preventing water from permeating into a solid preparation, whereby a sufficient disintegrating force was not achieved (see Comparative Example 4 of the present application).
PATENT DOCUMENT 17 describes a method for producing a tablet which is characterized by comprising molding a tablet by a compression molding method using, as a powder binder, rice starch and/or a rice starch derivative having a water content of 6 to 14% mass. It is described that the rice starch of this PATENT DOCUMENT has the primary particle with an average particle diameter of 4.8 μm in the dry state, and hence it is different from the present invention which has the primary article of 25 to 80 μm. Further, the production method of this document is also different from that of the present invention in the respect that there is no step of preparing a starch slurry or heating the starch slurry as described that the heat treatment was carried out for at least 30 minutes at a temperature of 75° C. or higher, followed by adjusting water content thereof.
PATENT DOCUMENT 18 describes a method for producing a granulated composition which is characterized by comprising wet granulating particulates containing one or more active ingredients having a solubility in water of 0.0001 to 10 g/L using, as a binder, a functional starch powder having a water retention capacity of 400% or higher, a gel indentation load of 100 to 3000 g, containing 40 to 95% of water soluble components. PATENT DOCUMENT 19 describes a method for producing a granulated composition which is characterized by comprising wet granulating particulates containing one or more active ingredients using, as a binder, a functional starch powder having a water retention capacity of 400% or higher, containing 40 to 95% by weight of water soluble components, having a gel indentation load of 100 g or more and less than 200 g. These PATENT DOCUMENTS are different from the present invention in the aspect of the amount range of the water soluble component. The water soluble component is described to be a value expressing the amount of the paste component which was gelatinized and become water soluble by heat treatment of the starch powder, namely the starch powder has 40 to 95% by weight of itself been gelatinized and is also different in the particle structure from the processed starch of the present invention which has the outer shell structure derived from raw starch. Further, these PATENT DOCUMENTS describe a production method comprising steps of further heating at 60 to 150° C. in the presence of water a starch material heat-treated using steam at 100 to 130° C. under a reduced pressure and swelling the starch particles of the starch material, and steps of subsequently drying the swollen starch particles and obtaining a powder mixture comprising the starch particle, and amylose and amylopectin present outside the starch particle. However, in Examples in which the above steps were carried out, the heat treatments were performed in the presence of water at a temperature of 95 to 120° C., exceeding 90° C., and the production method of these documents are different from that of the present invention in the aspect of the heat temperature in the presence of water in the step after a starch slurry is prepared. In this PATENT DOCUMENT, as a result of the heat treatment at a temperature exceeding 90° C., the outer shell structure derived from raw starch is destructed as described to read amylose and amylopectin present outside the starch particle, and the water soluble components are contained in an amount of 10% by weight or more preventing water from permeating into a solid preparation, whereby a sufficient disintegrating force was not achieved.
PATENT DOCUMENT 20 describes a solid pharmaceutical preparation containing (a) a drug and (b) 10 to 90% by weight of a pregelatinized starch. In this patent, the drug and the starch are both gelatinized, whereas only the starch is gelatinized in the present invention, where the difference lies.
In addition to the processed starch in which a raw starch is physically modified, the disintegrating properties of starches have been enhanced by chemical treatment using a crosslinking agent, or the like, as shown in PATENT DOCUMENTS 21 to 28.
PATENT DOCUMENT 10 describes a rapid swelling starch containing less than 2% by weight of a cold water soluble component (which corresponds to the water soluble component of the present invention) and having a changed crystal structure with a size identical with or smaller than natural starch. The processed starch of the present invention has a different amount range of the water soluble components from the rapid swelling starch. The processed starch of the present invention has an average particle size of the primary particles of 25 to 80 μm in the dry state, larger than a natural starch material, and is different from the starch of PATENT DOCUMENT 10 in the aspect of having an average particle size larger than a natural starch. Further, the PATENT DOCUMENT describes that when the rapid swelling starch is observed using a microscope in the dry state, the polarized cross somewhat irregular and different from that of a natural particulate but extremely distinct is found. This is different in the aspect of the particle structure from the processed starch of the present invention which is nonbirefringent particles. Furthermore, it is described that a part of the starch crystallinity needs to be inhibited before the removal/destruction treatment to obtain the rapid swelling starch of this patent. The inhibition means a treatment by a chemically modified reagent such as an organic solvent or an inhibitor which makes it different from the present invention in the aspect of involving the chemical treatment.
PATENT DOCUMENT 21 discloses a disintegrant containing as a main ingredient a low swelling starch powder which is crosslinked and pregelatinized, PATENT DOCUMENT 22 discloses a crosslinked pregelatinized starch, PATENT DOCUMENT 23 discloses a crosslinked amylose, PATENT DOCUMENT 24 discloses a starch which is hydrolyzed with an acid or an enzyme, PATENT DOCUMENT 25 discloses starch ether, PATENT DOCUMENT 26 discloses an enzymatically treated glucose polymer, PATENT DOCUMENT 27 discloses an enzymatically decomposed starch, PATENT DOCUMENT 28 discloses a starch obtained by heat dehydration after alkali treatment followed by heat treatment. However, the production methods of these documents require the use of an expensive organic solvent or reagent, alkali, enzyme, or the like, and involve complicated steps, consequently incurring high cost, and the influence by a remained organic solvent or reagent, alkali, enzyme, or the like, caused failure to always provide satisfactory starch in respect of the safety and stability of an active ingredient.
As described above, no prior art currently provides a very commonly eaten, highly safe disintegrant of a natural material origin which has a high disintegrating force even when added in a small amount as well as has a low reactivity to an active ingredient and little hygroscopicity, hence has good preparation storage stability, and further obtained by a method obviating chemical treatment. Such a disintegrant has been in demand.    PATENT DOCUMENT 1: JP 58-32828 A    PATENT DOCUMENT 2: U.S. Pat. No. 5,164,014    PATENT DOCUMENT 3: JP 62-7201 B    PATENT DOCUMENT 4: JP 53-5725 B    PATENT DOCUMENT 5: JP 58-27774 B    PATENT DOCUMENT 6: JP 59-47600 B (U.S. Pat. No. 4,447,601)    PATENT DOCUMENT 7: Japanese Patent No. 3004758    PATENT DOCUMENT 8: JP 56-11689 B    PATENT DOCUMENT 9: JP 2006-45222 A    PATENT DOCUMENT 10: JP 2004-238622 A    PATENT DOCUMENT 11: JP 11-269202 A (U.S. Pat. No. 6,143,324)    PATENT DOCUMENT 12: JP 2001-39894 A    PATENT DOCUMENT 13: U.S. Pat. No. 4,072,535    PATENT DOCUMENT 14: U.S. Pat. No. 3,622,677 (JP 46-21471 A)    PATENT DOCUMENT 15: JP 48-68726 A    PATENT DOCUMENT 16: WO2005/005484    PATENT DOCUMENT 17: JP 2006-176496 A    PATENT DOCUMENT 18: JP 2007-001875 A    PATENT DOCUMENT 19: JP 2007-001999 A    PATENT DOCUMENT 20: JP 2006-001924 A    PATENT DOCUMENT 21: JP 63-7531 B    PATENT DOCUMENT 22: U.S. Pat. No. 4,369,308    PATENT DOCUMENT 23: JP 8-507769 A    PATENT DOCUMENT 24: U.S. Pat. No. 455,177    PATENT DOCUMENT 25: JP 52-66619 A    PATENT DOCUMENT 26: JP 2005-213496 A    PATENT DOCUMENT 27: JP 2004-137230 A    PATENT DOCUMENT 28: WO1996/022110